Hormones such as the indole hormone, melatonin, are widely distributed in both plant and animal sources. Melatonin can be found in human milk, bananas, beets, cucumbers, and tomatoes. Chemically, melatonin is N-acetyl-5-methoxytryptamine, a derivative of serotonin, which in turn is derived from tryptophan. Melatonin is a ubiquitous natural neurotransmitter-like compound produced primarily by the pineal gland, and is involved in numerous aspects of the biological and physiologic regulation of body functions.
See, e.g., Malhotra, S., et al., Medscape General Medicine 2004; 6(2), 46; and www.nlm.nih.gov/medlineplus/print/druginfo/natural/patient-melatonin.html for general discussion.
The role of endogenous melatonin in circadian rhythm disturbances and sleep disorders is well established. Some studies have shown that melatonin may also be effective in breast cancer, fibrocystic breast diseases, and colon cancer. Melatonin has been shown to modify immunity, the stress response, and certain aspects of the aging process; some studies have demonstrated improvements in sleep disturbances and “sundowning” in patients with Alzheimer's disease. The antioxidant role of melatonin may be of potential use for conditions in which oxidative stress is involved in the pathophysiologic processes. The multiplicity of actions and variety of biological effects of melatonin suggest the potential for a range of clinical and wellness-enhancing uses, especially considering that as one ages, the production of this key hormone goes into steady decline. Indeed, for an octogenarian, the amount produced is quite nominal.
Through melatonin release, the pineal gland maintains the internal clock governing the natural rhythms of body function. This apparent clock-setting property of melatonin has led to the suggestion that it is a “chronobiotic” substance that alters and potentially normalizes biological rhythms and adjusts the timing of other critical processes and biomolecules (hormones, neurotransmitters, etc.) that, in turn, exert numerous peripheral actions. The sleep-inducing effects of melatonin have advantages over conventional hypnotics, since melatonin, itself, is not a hypnotic drug. Melatonin only induces a natural state of sleepiness, and does not have the adverse side-effects of conventional hypnotics and prescription sleeping aids.
Melatonin has previously been used pharmaceutically, and has been prepared for oral administration (see, e.g., WO1995/003043). These preparations include melatonin formulated with a cyclodextrin (WO 1999/047175), and as a microemulsion (U.S. Pat. No. 5,362,745). However, as with most oral preparations, it can take more than 30 minutes after administration for the blood plasma concentration of melatonin to reach its peak. Goldberg, M J, Bergstrom, R F R, Smith, B P, Simcox, E A, Thomasson, H R, Shipley, L A: Sleep Research 1997: 26:101. This is due, in part, to the need for gastrointestinal absorption to occur before the melatonin is available in the bloodstream. Further, melatonin's oral bioavailability is poor and erratic. Melatonin's absolute oral bioavailability has been shown to be approximately 15% and peak plasma concentrations can vary over 20 fold range. DeMuro R L, Nafziger A N, Blask D E, Menhinick A M, Bertino J S: Journal of Clinical Pharmacology 2000: 40; 781; Di W L, Kadva A, Johnston A, Silman R: New England Journal of Medcine 1997: 336; vol. 14, 1028. Thus, oral administration of melatonin in currently available preparations does not provide for rapid onset of action, and its poor and erratic GI absorption make it an unsuitable route of administration.
Several sublingual, buccal, orally dissolving tablets and films containing melatonin are also available commercially. For example, transmucosal formulations are described in WO 1996/030013 and U.S. Pat. No. 5,688,520. However, in these formulations, melatonin is compounded in its undissolved, or solid, state. For any drug to be absorbed into the bloodstream, it must be dissolved, i.e., in solution. Due to melatonin's poor water solubility much of the dosage from a currently available preparation is swallowed undissolved in the saliva, leading to poor and erratic absorption in the GI tract. Accordingly, hormone drugs such as melatonin having low to poor water solubility, are expected to be poorly suited for buccal or sublingual administration.
Other routes of administration for melatonin, including nasal and oral sprays have been considered. U.S. Pat. No. 6,007,834. However, sprays are less desirable because of inherent compliance issues such as improper manipulation of the actuator, swallowing of the dosage before dissolution of the drug, and the restrictions on usage when the patient has sinus congestion or a head cold. This again leads to erratic and poor melatonin bioavailability. Therefore sprays are not the optimal route for routine melatonin administration.
Accordingly, there is a need in the medical and pharmaceutical arts to provide an oral dosage form, preferably for sublingual or buccal administration, wherein the subject dosage form can provide rapid and consistent delivery of a hormone having low to poor water solubility, such as melatonin. This need is met by the subject composition, as well as its method of preparation and administration. The subject melatonin formulation can advantageously be useful to administer the drug to a patient in significantly less time and with more consistent and higher bioavailability than previously available dosage forms. Therefore, this invention as claimed, provides a unique composition, delivery system and method of administration for melatonin and other hormones having low to poor water solubility.